Substituted quinolizines



United States Patent 3,336,315 SUBSTITUTED QUINOLIZINES Robert I.Meltzer, Rockaway, and Richard E. Brown,

Hanover, NJ., assignors to Warner-Lambert Pharmaceutical Company, MorrisPlains, N.J., a corporation This is a divisional application ofapplication Ser. No. 248,872, filed Jan. 2, 1963.

This invention relates to novel substituted quinolizines having thefollowing structural formula:

I Q D A I B R III I R5 R1;

R N R: N

B B R2 2 V VI Ra R4 4 R1 \N 1 N VII VII wherein R and R each representshydrogen, hydroxy or lower alkoxy such as methoxy or methylene dioxy;

3,336,315 Patented Aug. 15, 1967 R represents hydrogen or lower alkylsuch as methyl or ethyl; R represents hydrogen, lower alkyl such asmethyl or ethyl, alkenyl such as vinyl, alkynyl such as ethynyl,

.or alkoxy such as ethoxy;R represents hydrogen, hy-

droxy, acyloxy, alkoxy,

-C0CH COCH OH, COOEt, COOH or C in which R and R may be hydrogen, loweralkyl or R and R taken together with the nitrogen to which they areattached form a heterocyclic radical such as or R and R taken togetherwith the carbon atom to which they are attached represent a keto radicalsuch as or a cyclic ketal radical such as and to the nontoxicpharmaceutically acceptable acid addition and quarternary ammonium saltsthereof.

The compounds of this invention are substituted quinolizines of the ringsystem comprised of the four rings denoted by A, B, C and D of the aboveformulas. When Ring D is a 5-membered ring such as the substituents arein the bracketed positions which follow: R (9), R (8), R (12a), R (1)and R (1) and when Ring D is a 6-membered ring such as the substituentsare in the bracketed positions which fol- 3 low: R R (9), R (13a), R (1)and R (1). The numbering of these ring systems is indicated below:

4 ture is used the compound 3,3a,5,6,10b,11,12,12a-octahydro 8 hydroxy12a methyl benzo[a]cyclopenta[f] The above compounds, on treatment withan alkali, undergo a shift of the azomethine double bond according tothe usual behavior of partially hydrogenated quinolizium compounds.Thus, for example, Compound I on treatment with an alkali metalhydroxide will result in the formation of a compound of the formula:

These compounds are also within the scope of this invention.

This invention also relates to a new and novel method of preparing theabove compounds and to novel intermediates obtained during thesynthesis. Exemplary of the new and novel qinolizines are:

invention resemble the steroid compounds structurally and can beconsidered to be azasteroids. If asteroid nomenclaquinolizin-l (2H)-onewhich has the following structural formula:

can also be named a stereo isomer of D,L8-azaestrone.

The new and novel compounds of this invention have interestingpharmacological activity and are useful in the treatment of shock andcirculatory collapse of the mammalian body such as dogs, rats, etc. Theyalso possess steroidal-like activity. In order to use these compounds asanti-shock agents, these compounds may be combined with an inertpharmaceutical carrier to form dosage forms such as tablets, elixirs,and solutions for injection, with the active ingredient being presentfrom about 0.1 mg. to mg. per dosage unit. These compounds may beadministered orally or by intramuscular injection at a dose of about 0.1mg. to 100 mg. several times daily. In addition, they are valuableintermediates in the production of other compounds of this substitutedquinolizine structure.

We have found that compounds of this invention may be produced inaccordance with the reactions as exemplified in the following series ofequations. The symbols R R R R and R used hereinafter are the same asdefined above.

Step I involves the condensation of substituted phenylalkylamines suchas R1 NHa by refluxing for about 3 to 6 hours in an inert organicsolvent such as Xylene with an equal molar ratio of a keto ester or acidsuch as carbalkoxyethyl cyclopentanone of the formula:

0 H m l O 0 Et to obtain a yellow oily compound of the structure Theabove compound may be cyclized by refluxing with phosphorous oxychlorideto obtain a compound of the structure Air Alternatively, the compoundmay be reduced in accordance with Step II before it is cyclized. We havealso fiound that the substituted phenylalkylamines may also be condensedwith a keto ester of acid such as 1OOEt to give a compound of thestructure We have also found that when there is a keto group attached toring D the reduction of the double bond in ring D also results in thereduction of the ketone to the corresponding alcohol such as In the casewhere R is hydrogen, this reduction is preferably carried out in thepresence of an alkali.

Step III involves the cyclization of the compounds ob-- tained inaccordance with Step II. The cyclization is effected by refluxing with aslight excess of phosphorous oxychloride to obtain compounds of thestructure and Br- B:

respectively.

When an OH group is present on ring D such as it is desirable to protectthe OH group when the compound is cyclized. We have found that the OHmay be protected by treating the parent compound bearing the OHsubstituent with carboxylic acid anhydrides such as acetic anhydride,and after the cyclization has been completed the OH group is restored byboiling with strong mineral acid. When the keto group is the desiredsubstituent on ring D, the corresponding alcohol as obtained in Step IImay be treated with chromic anhydride in acetone. This treatment resultsin the conversion of the --OH group to a keto group.

Before cyclization the keto group may also be converted to a cyclicketal group by treating a solution in benzene of the compound bearingthe ketone substituent with ethylene glycol in the presence of an acidcatalyst such as toluene sulfonic acid. The conversion of the hydroxygroup to a ketone may also be efiected after the cyclization of theparent compound by treatment of the hydroxy compound with chromicanhydride in acetone.

We have also found that compounds having a lower alkyl substituent suchas methyl at position 13 may be produced, for example, by firstcondensing a substituted phenylalkylamine such asm-methoxyphenethylamine with a keto ester such as2-methyl-2-(fi-carboxyethyl)3-carboxycyclopentanane to produce acompound of the formula:

MeO

The order of Steps II and III are interchangeable in that reduction StepII may be preceded by the cyclization Step III which may then befollowed by the reduction if the reduced product is desired. The orderof the steps is not essential and is dependent on the ultimate productdesired, although the reduction of Step II prior to Step III ispreferable when R, is hydrogen. The acid chloride group introduced inthe above example may serve as an intermediate to the preparation ofmany derivatives such as ester, amides, ketones, anhydrides, amines,alcohols, and the like.

We have also found that compounds such as 11, III, IV, V, VI and VIIIwhich contain a quaternary nitrogen atom can be reduced to thecorresponding tertiary nitrogen by treatment with gaseous hydrogen in aninert solvent in the presence of a noble metal catalyst such as platinumor palladium on carbon.

In addition, we have also found that compounds wherein the substituentsR and R are lower alkoxy can be dealkylated employing hydrobromic orhydroiodic acids.

In quaternary salts such as II, two diasterioisomeric forms of thisstructure are possible depending upon the cis or trans fusion of the Cand D rings. Each of these diasterioisomeric forms on reduction of itsazomethine linkage will give rise to two additional disasterioisomericforms depending upon the configuration of hydrogen atom at position 12aor 13a. All these four diasterioisomen'c forms are capable of beingresolved into optically active antipodes.

The following examples are included in order further to illustrate theinvention.

EXAMPLE 1 1,2,3,4,4a,6,7,12,13,13a-dez-ahydr 9JO-dimethoxy-I-ox0-dibenzo [a,f] quinolizium perchlorate A solution of 5.0 g. of1-(3,4dimethoxyphenethyl)- octahydro--hydIoxy-2-(1H)quinoline in 500 ml.reagent grade acetone is cooled to 2 C. and treated all at once withvigorous stirring with 4.5 ml. of 8 N chromic anhydride in aqueoussulfuric acid. After stirring for 5 minutes at 2 C. 100 ml. of water areadded, and the acetone is removed by distillation under reducedpressure. The green aqueous solution is extracted four times withbenzene. The benzene solution is washed with 5% NaHCO solution andwater, dried, and treated with 5 ml. ethylene glycol and a few crystalsof p-toluene sulfonic acid. This mixture is refluxed four hours under aDean-Stark trap, then washed two times with 5% aqueous NaHCO solution.The benzene solution is dried over MgSO and treated with 25 ml.phosphorous oxychloride and refluxed for 1 /2 hours. The dark redsolution is concentrated to dryness under vacuum, the oily residuedissolved in 2 N HCl and heated /2 hour on the steam bath. Aftercooling, the solution is treated slowly with 60% perchloric acid. Thegummy precipitate is rubbed until solidification takes place. The yellowslurry is cooled for 16-24 hours and filtered to give1,2,3,4,4a,6,7,12,13,13a-decahydro- 9,10-dimethoxy-1oxo-dibenzo[a,f]quinolizium perchlorate as a yellow solid, M.P. 206209C. The recrystallization product from 80% ethanol melts at 210-214" C.

EXAMPLE 2 2,3,3a,5,6,1 1 ,12,12a-0cfahydr0-8,9-dimethoxy-1H-benzm[a]oycl0penta[;f]quinolizinium diehlorophosphate To a solution of 6.0 g.of 1-(3,4-dimethoxyphenethyl)- octahydro-ZH-l-pyrindin-Z-one in 90 ml.benzene is added 24 ml. phosphorous oxychloride and the solutionrefluxed for 1 /2 hours. The solution is cooled, diluted with 300 ml.petroleum ether, left two hours at 20-25 C. to obtain2,3,3a,5,6,ll,12,l2a-oetahydro-8,9-dimethoxy-1H benzo[a]cyclopental[f]quinolizinium diehlorophosphate in the form of aprecipitated solid. It is recrystallized from cold ethanol and ether toM.P. 147-148" C.

8 EXAMPLE 3 2,3,5 ,6,1 I ,1 Z-hexahydro-8,9-dimethoxy-1 H -benz0[a]cycyclopenrafi]quinolizinium diehlorophosphate" To a solution of 12 g.of 1-(3,4-dimethoxyphenethyl)- 1,3,4,5,6,7 hexahydro-2H-l-pyrindin-2-onein 180 ml. benzene is added 48 ml. phosphorous oxychloride and thesolution refluxed for two hours. The solution is cooled, diluted with500 ml. petroleum ether, left at 2025 C. for 16-24 hours. Theprecipitated oil is dissolved in 20 ml. acetone, scratched to inducecrystallization and the slurry filtered to obtain2,3,5,6,ll,12-hexahydro-8,9-dimethoxy-lH-benzo [a] cyclopenta[f]quinolizinium dichlorophosphate in the form of a yellow solid whichafter recrystallization from isopropyl alcohol melts at 149- 156 C.

EXAMPLE 4 2,3,5 ,6,1 1 ,12-hexahydro-8-methxoy-1H-benzo [a]cyclopenta[f] quinolizinium diehlorophosphate In the same way asdescribed in Example 3, 12 g. of1,3,4,5,6,7-hexahydro-l-(m-methoxyphenethyl) 2H 1- pyrindin-Z-one givesafter recrystallization from acetone2,3,5,6,11,12-hexahydro-8-methoxy-1H benzo[a]cyclopenta[f]quinoliziniumdiehlorophosphate in the form of oil-white crystals, M.P. 179181 C.

EXAMPLE 5 2,3,3a,5 ,6 ,1 I ,12,12a-octahydro-8-methoxy-1Za-me'thyI-I- chloro-carbonyl-I H -benz0 [a] cycl0penta[ f] quinoliziniumdiehlorophosphate A solution of 5.0 g. ofoctahydro-l-(m-methoxyphenethyl)-4a-methyl-2-oXo-lH-lpyrindin-S-carboxylic acid in 50 ml. of phosphorous oxychloride isheated two hours at C. and evaporated to obtain2,3,3a,5,6,11,12,12aoctahydro-8-methoxy 12a methyl 1 chlorocarbonyl- 1Hbenzo[a]cyclopenta[f]quinolizinium diehlorophosphate as an oily residue.The oil is washed thoroughly with petroleum ether.

EXAMPLE 6 2,5,6,11,12,I2a-hexahydro-8,9 dimethoxy 12a methyl- 1carboxy-IH benzo [a]cyclopentafi]quinolizinium percholomte In the sameway as described in Example 5, 4.5 g. of1-(3,4-dimethoxyphenethyl)-2,3,4,4a,5,6-hexahydro4amethyl-Z-oxo-IH-l-pyrindin-S-carboxylic acid gives after reaction2,5,6,11,12,12a-hexahydro-8,9 dimethoxy 12amethyl-1carboxy-1H benzo[a]cyclopenta[f] quinolizinium percholorate in the form of a yellowcrystalline salt which is recrystallized from ethanol-ether to a M.P. of218220 C.

EXAMPLE 7 2,3,3a,5,6,11,12,12a octahydro 8,9 dimethoxy 12amethyl-I 0x0IH-benzo[a]cyclopenta[f]quinolizinium perchlorate A solution of 3.0 g.of 1-(3,4-dimethoxyphenethyl)- tetrahydro-4a-methyl 1H 1pyrindin-2,5(3H,6H)-dione in a mixture of 70 ml. benzene and 10 ml.phosphorous oxychloride is refluxed 15 minutes, then'evaporated to anoil. The oil is taken up in water and a 10% solution of perchloric acidadded slowly until precipitation is complete. The slurry is cooled for20 hours at 10 to obtain 2,3,3a,5,6,1l,12,l2a octahydro 8,9 dimethoxy12amethyl-l-oxo 1H benzo[a]cyclopenta[f]quinolizinium perchlorate in theform of a yellow solid. The recrystallized form from ethanol-ether meltsat 217-220 C.

EXAMPLE 8 2,5,6,11,12,12a-hexahydr0 8,9 dimethoxy I2a-methyll-oxo 1Hbenzo [a] cyclopentafi] quinolizinium perchlorate In the same way asdescribed in Example 7, 0.2 g. of 1-(3,4-dimethoxyphenethyl) 4,4'adihydro 4a methyl- 9 lH-l-pyrindin 2,5(3H,6H) dione gives2,5,6,11,l2,12ahexahydro-8,9-dimethoxy-IZa-methyl-l-oxo 1H benzo-[a]cyclopenta[f] quinolizinium perchlorate in the form of a yellow solidwhich after recrystallization from methanolether gives M.P. 242245 C.

EXAMPLE 9 2,5,6,11,12,12a-hexahydr 8,9 dimethoxyIZa-methylchlorocarbonyl 1H benzo [a]cyclop-enta[f]quin0- liziniumdichlorophosphate EXAMPLE 10 2,5,6,11,12,12a hexahydro 8 methoxy 12amethylchlorocarbonyl 1H benz0[a]cyclopenta[f] quinclizinumdichlorophosphate A solution of 17.5 g. of2,3,4,4a,5,6-hexahydro-l-(mmethoxyphenethyl)-4a-methyl-Z-oxo 1H 1pyrindin- S-carboxylic acid in 150 ml. phosphorous oxychloride is heated3 hours at 100 C. and evaporated under reduced pressure to obtain2,5,6,11,12,12a-hexahydro-8-methoxy- 12a-methyl-1 chloroearbonyl 1Hbenzo[a]cyc1openta [f] quinolizinium dichlorophosphate in the form of anoil.

EXAMPLE 1 1 2 (13a),3,4,4a,6,7,12,13-0ctahydr0-9,1O-dimethoxydibenzo[11, f] -quin0lizinium perchlorate To a solution of 0.5 g. of1-(3-,4-dimethoxyphenethyl)- octahydro--hydroxy-2(1H)-quinolone in 10 ml. benzene is added 2 ml. phosphorous oxychloride. The mixture isrefluxed for two hours, evaporated to an oil and the oil is dissolved inwater. The aqueous solution is treated dropwise with a 10% aqueoussolution of perchloric acid until precipitation is complete to obtain2(13a),3,4,4a,6,7,12, 13-octahydro-9,1 0 dimethoxydibenzo[a,f]quinolizinium perchlorate. The perchlorate salt is filtered and can berecrystallized from methanol to M.P. 223-225 C.

EXAMPLE 12 1,2,3,4,4a,6,7,12,13,13a decahydro 1 acetoxy 9,10-dimethoxydibenzo [a, quinolizinium perchlorate In the same way asdescribed in Example 11, 0.25 g. of 1-( 3,4dimethoxyp'henethyl)octahydro 5 hydroxy- 2(1H)-quinolone acetate givesthe yellow perchlorate salt 1,2,3,4,4a,6,7,12,13,13a decahydro 1 acetoxy9,10- dimethoxydibenzo[a,f]quinolizinium perchlorate which can berecrystallized from methanol to yellow needles, M.P. 246.5-248 C.

EXAMPLE 13 1,2,3,6,7,12,13,13a-0ctahydr0-9,10-dimethoxy-1-0x0-13amethyldibenzo [aj] quinolizinium dichloro phosphateA solution of 1.8 g. of 1-(3,4-dimethoxyphenethyl)-3,4,6,7-tetrahydro-4a-methyl 2,5(1H,4aH) quinolinedione in a mixture of70 ml. benzene and 7 m1. phosphorous oxychloride is refluxed for 1 /2hours. The precipitated yellow solid is filtered and recrystallized fromcold methanol-ether to obtain 1,2,3,6,7,12,13,13a-octahydro-9,10-dimethoxy-1 0x0 13a methyldibenzo[a,f]quinoliziniumdichlorophosphate in the form of bright yellow crystals, M.P. 166168 C.

EXAMPLE 14 2,3,3a,5,6,l 1,12,]2a-octahydro-8,9-dimethoxy-12a-methyl-1-benz0[a]cycl0penta[f]quinolizinium iodide A solutionof 37.4 g. ofoctahydro-1-(3,4-dimethoxyphenethyl)-4a-methyl-2H-l-pyrindine-Z-one in amixture of 350 ml. benzene and 100 ml. phosphorous oxychloride isrefluxed two hours and concentrated to an oil. The oil is dissolved inml. methanol and 250 m1. of 20% sodium hydroxide solution is addedslowly with cooling. The slurry is cooled two hours at 10 C. and thesolid is filtered. The residue is dissolved in an excess of 10% aqueoushydriodic acid and the solution evaporated in reduced pressure to obtain2,3,3a,5,6,11,12,12a-octahydro- 8,9-dirnethoxy-l2a methyl 1H benzo[a]cyclopenta[f] quinolizinium iodide in the form of an oil. The oilcrystallizes on rubbing with isopropyl alcohol and is recrystallizedfrom methanol-ether to give yellow crystals, M.P. 205-207 C.

EXXAMPLE 15 1,2,3,4,4a,6,7,12,13,13a decahydro 1 hydroxy 9-meth0xydibenz0[a,f]quinolizinium bromide A solution of 1.0 g. ofoctahydro-S-acetoxy-l(m-methoxyphenethyl)-2(1H)-quinolone is refluxedfor three hours with 50 ml. of 2 N hydrobromic acid. The solution isevaporated to dryness. The residue crystallizes from isopropanol to give1,2,3,4,4a,6,7,12,13,13a-decahydro-l-hydroxy 9methoxydibenzo[a,f]quinolizinium bromide in the form of a yellow solidwhich is recrystallized from methanol-ether, M.P. 2l9220 C.

EXAMPLE 16 l,2,3,4,4a,6,7,12,13,13a-decahydr0-9-meth0xy-1-0x0- di b enzo[a, f] quinol izinim bromide A solution of 55.5 g. of1,2,3,4,4a,6,7,12,13,13a-decahydro 1 hydroxy 9 methoxydibenzo[a,f]quinolizinium perchlorate in 4 liters of reagent grade acetone at 2 C.is treated over a 5 minute period with rapid stirring with 82 ml. of 8 Nchromic anhydride in sulfuric acid. After addition is complete themixture is stirred for 5 minutes. A rapid stream of gaseous sulfurdioxide is passed through the mixture until precipitation of chromicsalts is complete. The mixture is filtered and the acetone removed byevaporation. The oily residue is dissolved in 3 liters of hot water,cooled to 50 C. and poured into a slurry of ice and 500 ml. of 50%sodium hydroxide solution. The precipitated oil is extracted with 250m1. portions of methylene chloride. The combined extracts are dried overmagnesium sulfate and dry hydrogen bromide passed in until precipitationof the yellow oil is complete. The methylene chloride is evaporated andthe oily residue dissolved in 100 ml. isopropyl alcohol and cooled for72 hours to obtain 1,2,3,4,4a,6,7,12,13,13a decahydro 9- methoxy 1oxodibenzo[ a,f]quinolizinium bromide in the form of a yellow solid. Therecrystallized form from ethanol-ether melts at 210-212 C.

EXAMPLE l7 2,5,6,I1,12,12a hexahydro 8 methoxy 1 0x0 12amethyl 1Hbenz0[a] cyclopenta [f] quinolizium perchlorate A solution of 0.7 g. of4,4a-dihydro-1-(m-methoxyphenethyl) 4amethyl-1H-1-pyridine-2,5(3H,6H)dione in a mixture of 27 ml. benzene and2.7 ml. phosphorus oxychloride is refluxed 1 /2 hours. The mixture isdecanted from the precipitated black tar and evaporated to an oil. Theoil is boiled with 10 ml. water, cooled and decanted from more insolublegum. The aqueous solution is treated with a 10% solution of perchloricacid until precipitation of the oil is complete. The oil crystallizes onrubbing with isopropyl alcohol and is recrystallized from isopropylalcohol to obtain 2,5,6, 11,12,12a hexahydro 8 methoxy 1 oxo 12amethyl1H benzo[a]cyclopenta[f]quinolizium perchlorate, M.P. ZOO-204 C.

1 1 EXAMPLE 18 2,3,3a,5,6,11,12,12a octahydro 8 methoxy 1 x0- 1211methyl 1H benzo[a]cyclopentaU]quinolizinium bromide A solution of 3.9 g.of tetrahydro 1 (rn-methoxyphenethyl) 4a methyl 1H 1 pyridine 2,5(3H,6H)dione in 30 m1. benzene is refluxed with 13 ml. phosphorous oxychloridefor 15 minutes. The benzene and phosphorous oxychloride are removed andthe residual red oil dissolved by heating in 25 ml. water. Aftercooling, the solution is extracted with ether and the yellow aqueoussolution cooled and made basic with dilute sodium hydroxide. The oilyprecipitate is extracted with ether and dry gaseous hydrogen bromide ispassed through the ethereal extract. The oily quaternary bromidesolidifies on rubbing with acetonit-rile to give 2,3, 3a, 5,6,11,12,12aoctahydro 8 methoxy 1 oxol2a methyl 1Hbenzo[a]cyclopenta[f]quinolizinium bromide in the form of yellowneedles. After recrystallization from ethyl-acetate-acetonitrile theproduct melts at 211-213 C.

EXAMPLE 19 I,2,3,6,7,12,13,13a octahydro 9,10 dimethoxy13amethyldibenz0[a,f]quinolizinium bromide In the same way as describedin Example 18, 20 g. of 1 (3,4 dimethoxyphenethyl) 3,4,4a,5,6,7hexahydro 4a methyl 2(1H) quinolone gives 1,2,3,6, 7,12,13,13a octahydro9,10 dimethoxy 13a methyldibenzo[a,f]quinolizinium bromide in the formof a yellow solid which after recrystallization from isopropylalcohol-ether melts at 173-174" C.

EXAMPLE 20 2,3,3a,5,6,11,12,12a octahydro 8,9 dihydroxy 1H- benzo [a]cyclopenta [f] quinolizinium bromide A solution of 1.0 g. of2,3,3a,5,6,11,12,12a-octahydro- 8,9 dimethoxy 1Hbenzo[a]cyclopenta[f]quinolizinium dichlorophosphate in ml. of 48%hydrob-romic acid is refluxed for 4 hours. The excess acid is removed bydistillation under reduced pressure. The oil crystallizes on scratchingwith ethanol and is recrystallized from ethanol-ether to obtain2,3,3a,5,6,11,12,12a-octahydro- 8,9 dihydroxy 1Hbenzo[a]cyclopenta[f]quinolizinium bromide melting at 222-224" C.

EXAMPLE 21 1,2,3,4,4a,6,7,12,13,13a decahydro 9,10 dihydroxy-I3a-methyldibenz0[a,f]quinolizinium bromide In the same way as describedin Example 20, 10 g. of 2,3,4,4a,6,7,13,13a octahydro 9,10 dimethoxy13amethyl-1H-dibenzo[a,f]quinolizine are demet'hylated to give1,2,3,4,4a,6,7,12,13,13a decahydro 9,10 dihydroxy 13amethyldibenzo[a,f]quinolizinium bromide as yellow crystals which, afterbeing recrystallized from methanol-ether melt at 256-258 C.

EXAMPLE 22 1,2,3,6,7,12,13,13a octahydro 9,10 dihydroxy13amethyldibenzo[a,,f]quin0lizinium' bromide In the same way asdescribed in Example 20, 2.4 g. of 1,2,3,6,7,12,13,13a octahydro 9,10dimethoxy- 13a methyldibenzo[a,f]quinolizinium bromide are demethylatedto give 1,2,3,6,7,12,13,13a octahydro 9,10- dihydroxy 13amethyldibenzo[a,f]quinolizinium bromide as yellow crystals which, afterrecrystallization from methanol-ether melt at 225227 C.

EXAMPLE 23 2,3,3a,5,6,11,12,12a octahydro 8,9 dihydroxy 12amethyl 1Hbenz0[a]cycl0penta[f]quinolizinium br0- mide In the same was asdescribed in Example 20, 6.0 g. of 2,3,3a,5,6,11,12,12a octahydro 8,9dimethoxy- 12 12a methyl 1H benzo[a]cyclopenta[f]quinolizinium bromideare demethylated to give 2,3,3a,5,6,l1,12,12aoctahydro 8,9 dihydroxy 12amethyl 1H benzo [a]cyclopenta[f]quinolizinium bromide as yellow crystalswhich, after being recrystallized from methanolether melt at 243-244 C.

EXAMPLE 24 1,2,3,4,4a,6,7,12,13,13a decahydro 9 hydroxy 1-oxodibenzo[a,f1quinolizinium bromide In the same way as described inExample 20, 6.0 g. of 1,2,3,4,4a,6,7,12,13,13a decahydro 9 methoxy 1-oxodibenzo[a,f]quinolizinium bromide are demethylated to give1,2,3,4,4a,6,7,12,13,13a decahydro 9 hydroxy- 1oxodibenzo[a,f]quinolizinium bromide as a yellow solid which, afterbeing recrystallized from methanolether melts at 241244 C.

EXAMPLE 25 1,2,3,4,4a,6,7,12,13,13a decahydro 1,9dihydroxydibenzo[a,f]quinolizinium bromide A solution of 6.1 g. of1,2,3,4,4a,6,7,12,13,l3a-decahydro 1 hydroxy 9methoxydibenzo[a,f]quinolizinium bromide in ml. of 48% hydrobromic acidis refluxed for 20 minutes then evaporated to an oil under reducedpressure. The oil crystallizes on rubbing with ethanol to obtain1,2,3,4,4a,6,7,12,l3,13a-decahydro-1,9-dihyd-roxydibenzo[a,f]quinolizinium bromide as a yellow solid which,after being recrystallized from ethanolether melts at 264267 C.

EXAMPLE 26 2,3,3a,5,6,11,12,12a octahydro 8 hydroxy 1H benzo[a]cycl0penta[f]quinolizinium bromide A solution of 9.3 g. of2,3,3a,5,6,11,12,12a-octahydro- 8 methoxy 1Hbenzo[a]cyclopenta[f]quinolizinium perchlorate in ml. acetone is cooledto 10 C. with ice and poured into 300 ml. of a 5% solution of sodiumhydroxide. The precipitated solid is filtered, dissolved in ml. of 48%hydrobromic acid and refluxed for 6 hours. The excess acid is removed bydistillation under reduced pressure to obtain 2,3,3a,5,6,11,l2,12aoctahydro 8 hydroxy 1H benzo[a]cyclopenta[f] quinolizinium bromide as asolid residue which, after being recrystallized (from methanol melts at275277 C.

It is understood that the foregoing detailed description is given merelyby way of illustration and that many variations may be made thereinwithout departing from the spirit of our invention.

Having described our invention, what we desire to secure by LettersPatent is:

1. A compound selected from the group consisting of those having theformulas: I

D C D R1 N R1 N B A B 2 R2- V VI R1 N R1 AN B B R2 R2 VII VIII wherein Rand R each is a member selected from the group consisting of hydrogen,hydroxy, and lower talkoxy, R is a member selected irom the groupconsisting of hydrogen, methyl and ethyl, R is a member selected fromthe group consisting of hydrogen, lower alkyl, alkoxy, alkenyl, and R isa member selected from the group consisting of hydrogen, hydroxy,acyloxy, of a carboxylic acid, alkoxy, COOH, COO-R in which R is loweralkyl,

n i O-C1 and 5N\ in which R, and R is each a member selected from thegroup consisting of hydrogen, and lower alkyl; and R and R takentogether with the carbon atom to which they .areattached form a memberselected from the group consisting of keto and cyclic keta-l.

2. The compound of claim 1 which is 2,5,6,11,12, 12ahexahydroS-methoxy-12a-methyl-l-chlorocanbonyl-IH- benzo [a] cyclopenta [f]quinolizinium dichlorophosphate.

3. The compound of claim 1 which is 2,3,3a,5,6,11,12, 12a octahydroS-methoxy-12a-methyl-1-chlorocarb0ny1- 1H benzo[a]cyclopenta[ f]quinolizinium dichlorophos phate.

4. The compound of claim 1 which is 2,3,3a,5,6,1l,12, 12a-octahydro 8methoxy 1H benzo[a]cyclopenta[f] quinolizin-ium bromide.

5. The compound of claim 1 which is 2,3,3 a,5,6,11,12, 12a octahydro 8hydroxy 1H-benzo[a] cyclopenta[f] quinolizini-um bromide.

6. The compound of claim 1 which is 2,3,5,6,11,12- hexahydro 8 methoxy1H benzoLa] cyclopenta[f] quinolizinium dichiorophosphate.

7. The compound of claim 1 which is 2,3,3a,5,6,11,12, 12a octahydro 8,9dimethoxy-1H-benzo[a]cyclopenta [f] quinolizinium dichlorophosphate.

8. The compound of claim 1 which is 2,3,5,6,11,12- hexahydro 8,9dimethoxy 1H-benzo[a]cyclopenta[f] quinoliziniurn dichlorophosphate.

9. The compound of claim 1 which is 2,3,3a,5,6,11,12, 12a octahydro 8,9dihydroxy-lH-benzo [:aJcyclopenta [f] q-uinolizinium bromide.

10. The compound of claim 1 which is 1,2,3,6,7,12,13, 13a octahyd-ro9,10 dimethoxy 1-oxo-13a-methyldibenzo[a,'f] quinoliz-iniumdichlorophosphate.

11. The compound of claim 1 which is 3,4,4a,6,7,12,13, 13a octahydro9,10 dimethoxydibenzo[a,f] quinolizinium perchlorate.

12. The compound of claim 1 which is 1,2,3,4,4a,6,7, 12,13,13a decahydro1 .acetoxy 9,10 dimethoxydibenzo [a,f] quinolizinium perchlorate.

13. The compound of claim 1 which is 1,2,3,4,4a,6,7, 12,13,13a decahydro1 hydroxy 9,10 dimethoxydibenzo a,f] quinolizinium bromide.

14. The compound of claim 1 which is 1,2,3,4,4a,6,7, 12,13,13a decahydro9,10 dimethoxy 1 oxo-dibenzo [a,f] quinolizinium bromide.

15. The compound of claim 1 which is 2,5,6,11,12,12-a hexahydro 8,9dimethoxy 12a methyl-l-chlorocarbonyllH- benzo a]cyclopenta[f]quinolizinium dichlorophosphate.

16. The compound of claim 1 which is 2,5,6,11,12,12ahexahydro 8,9dimethoxy 12a methyl l-oarboxy-IH- benzo a] cyclopenta [-f]quinoliziniurn perchlorate.

17. The compound of claim 1 which is 2,5,6,l1,12, 12a hexahydro 8methoxy 1 oxo-12a-methyl-1H- benzo[a] cyc1openta[f]quinoliziniumperchlorate.

18. The compound of claim 1 which is 2,3,3 a,5,6,11,12, 12a octahydro 8methoxy 1 oxo-12a-methyl-1H- benzoba]cyc1openta[f]quinoliziniumperchlorate.

19. The compound of claim 1 which is 1,2,3,4,4a,5,6, 12,13,13a decahydro9,10 dihydroxy 13a methyldibenzo [a,f] q-uinolizinium bromide.

20. The compound of claim 1 which is 1,2,3,6,7,12, 13,13a octahydro 9,10d-imethoxy 13'a-met'hy1di'benzo [a,f]quinolizinium bromide.

21. The compound of claim 1 which is 1,2,3,6,7,12,13, 13a --octahydro9,10 dihydroxy 13a methyldibenzo [a,f] quinolizinium bromide.

22. The compound of claim 1 which is 2,3,3a,5,6,11,12, 121a octahydro8,9 dimethoxy 12a methyl-lH-benzo [a] cyclopenta f] quinoliziniumbromide.

23. The compound of claim 1 which is 1,2,3,4,4-a,6,7, 12,13,13adecahydro 9 methoxy 1 oxodibenzo[a,f] quinolizinium bromide.

24. The compound of claim 1 which is 1,2,3,4,4a,6,7, 12,13,13a decahydro1 hydroxy 9 methoxydibenzo [a,f] quinolizinium bromide.

25. The compound of claim 1 which is l,2,3,4,4a,6,7, 12,13,13a decahydro9 hydroxy 1 oxodibenzo[a,f] quinolizinium bromide.

26. The compound of claim 1 which is 1,2,3,4,4a,6,7, 12,13,13-adecahydro 1,9 dihydroxydibenzo[a,f]quinoliz-inium bromide.

References Cited Kanaoka: Chem. Pharm. Bull, vol. 7, pp. 5957 (1959).

ALEX MAZEL, Primary Examiner. D. DAUS, Assistant Examiner.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THEFORMULAS:
 15. THE COMPOUND OF CLAIM 1 WHICH IS2,5,6,11,12,12AHEXAHYDRO - 8,9 - DIMETHOXY - 12A -METHYL-1-CHLOROCARBONYL-1H-BENZO(A)CYCLOPENTA(F)QUINOLIZINIUMDICHLOROPHOSPHATE.